Temporal lobe epilepsy associated with hippocampal sclerosis accounts for a major portion of disability suffered by persons with epilepsy. Invasive studies on these patients during evaluation for surgical treatment have revealed evidence for both enhanced inhibitory and excitatory mechanisms. Because two distinct types of ictal events have been demonstrated: (l) low voltage fast EEG onsets suggesting disinhibition and (2) hypersynchronous EEG onsets suggesting important inhibitory involvement, the enhanced inhibition observed in human epileptic hippocampus, and also in hippocampi of some epileptic animal models, may not only act as a homeostatic protective mechanism to maintain the interictal state, but also may contribute directly to the development of certain ictal events. We propose to carry out iterative parallel chronic in vivo experiments on rats with chronic limbic seizures following intrahippocampal kainic acid injections and patients with temporal lobe epilepsy, using unique microelectrode and microdialysis techniques available only at UCLA for patients and at Rutgers for rats. Measurements of spontaneous and evoked unit activity, field potentials and GABA, glutamate, aspartate, and opioid peptide release in chronically epileptic hippocampus and entorhinal cortex will be used to quantitatively test four hypotheses: (I) the interictal state of the epileptogenic human and rat hippocampus involves enhanced inhibition in some neuronal aggregates and enhanced excitation in others; (2) at least two distinct mechanisms of transition to ictus occur, one disinhibitory due to decreased inhibition and increased excitation, the other hypersynchronous, requiring both increased inhibition and increased excitation; (3) transition from a hypersynchronous ictal pattern to a disinhibitory ictal pattern reflects propagation to structures with different physiological and anatomical properties, rather than a change in the physiological properties of the structures initiating the seizure; and (4) disinhibitory type ictal events are associated with release of opioid peptides, which suppress unit discharges, while hypersynchronous type ictal events do not release opioid peptides and seizures terminate because the involved neuronal aggregates become desynchronized. Data obtained will be related to the location and degree of hippocampal cell loss, mossy fiber sprouting, and inhibitory hyperinnervation revealed from separate microanatomical studies carried out on tissue from these patients and animals. Patient studies will be used to validate the animal model and refine it when necessary, while the animal model will permit more experimental control over anatomical resolution and quantitative analyses. It is anticipated that this research will reveal pathophysiological substrates of temporal lobe epilepsy that: (I) differ from other forms of partial and generalized epilepsy; (2) account for the high incidence of medical refractoriness of this condition; and (3) provide insights into more effective approaches to pharmacological therapy.